Ataxia telangiectasia is a hereditary multi-systemic disease. The affected gene, ATM (ataxia telangiectasia mutated) encodes for a protein kinase which plays a role in cell cycle check points, DNA repair and apoptosis. Ischemic heart disease is the second major cause of death in individuals carrying a heterozygous mutation of ATM gene. However, the role of ATM in ischemic heart disease remains to be investigated. Using molecular, biochemical and genetic strategies, we provided evidence that ATM plays an important role in -adrenergic receptor-stimulated cardiac remodeling with effects on ventricular function, apoptosis and fibrosis. Our recently published and preliminary data, using myocardial infarction (MI) as a model of myocardial remodeling, demonstrate distinct changes in cardiac structure, function and remodeling between wild-type (WT) and ATM heterozygous knockout (hKO) hearts 7 days post-MI. Infarct size was comparable between the hKO and WT mice 7 days post-MI, however, infarct thickness was greater in hKO mice. hKO-MI group exhibited significant attenuation of LV dysfunction as analyzed by changes in percent fractional shortening and dilatation. Apoptosis, fibrosis and expression of a-smooth muscle actin (a marker for myofibroblasts) was higher, while expression of manganese superoxide dismutase (an antioxidant enzyme) was lower in hKO-MI hearts versus WT-MI. Activation of AMP activated protein kinase (AMPK; a key regulator of cellular energy homeostasis and mitochondrial biogenesis) and Akt, and expression of HIF-1a was lower, while activation of GSK-3 (a pro-apoptotic kinase) was higher in hKO-MI hearts. Kaplan-Meier survival analysis revealed reduced survival in hKO group 7-14 days post-MI, with impaired heart function and dilatation 14 days post-MI. In vitro, pharmacological inhibition of ATM induced oxidative stress, mitochondrial abnormalities and apoptosis in myocytes. These observations led to our hypothesis that alterations in the infarct structure due to the presence of increased number of myofibroblasts improve heart function during ATM deficiency early post- MI (=7 days). However, decreased AMPK activity and mitochondrial biogenesis shift the balance towards increased myocyte apoptosis, deterioration of heart function and enhanced mortality during ATM deficiency late post-MI (>7 days). Aim 1 will address, in vivo, the role of ATM in the activation of AMPK and mitochondrial biogenesis in the heart post-MI using WT and hKO mice. Aim 2 will investigate, in vivo, the beneficial effects of -AR antagonism and AMPK activation during ATM deficiency in the heart post- MI. Aim 3 will use myocytes isolated from the myocardium of adult WT and ATM deficient mice to get an insight into the mechanism by which ATM deficiency alters AMPK activity and mitochondrial biogenesis. These studies may help identify therapeutic targets to treat ischemic heart disease in A-T patients.